Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose‐coated polymeric nanocarriers, which can be bound by glucose transporter‐1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose‐ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non‐coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose‐modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.     

Amphiphilic Copolymers Shuttle Drugs Across the Blood–Brain Barrier

Medical treatment of diseases of the central nervous system requires transport of drugs across the blood–brain barrier (BBB). Here, it is extended previously in vitro experiments with a model compound to show that the non‐water‐soluble and brain‐impermeable drug domperidone (DOM) itself can be enriched in the brain by use of an amphiphilic copolymer as a carrier. This carrier consists of poly(N‐(2‐hydroxypropyl)‐methacrylamide), statistically copolymerized with 10 mol% hydrophobic lauryl methacrylate, into whose micellar aggregates DOM is noncovalently absorbed. As tested in a BBB model efficient transport of DOM across, the BBB is achievable over a wide range of formulations, containing 0.8 to 35.5 wt% domperidone per copolymer. In neither case, the polymer itself is translocated across the BBB model. In vivo experiments in mice show that already 10 min after intraperitoneal injection of the polymer/domperidone (PolyDOM) formulation, domperidone can be detected in blood and in the brain. Highest serum and brain levels of domperidone are detected 40 min after injection. At that time point serum domperidone is increased 48‐fold. Most importantly, domperidone is exclusively detectable in high amounts in the brain of PolyDOM injected mice and not in mice injected with bare domperidone.

     

Applying the Retro‐Enantio Approach To Obtain a Peptide Capable of Overcoming the Blood–Brain Barrier

The blood–brain barrier (BBB) is a formidable physical and enzymatic barrier that tightly controls the passage of molecules from the blood to the brain. In fact, less than 2 % of all potential neurotherapeutics are able to cross it. Here, by applying the retro‐enantio approach to a peptide that targets the transferrin receptor, a full protease‐resistant peptide with the capacity to act as a BBB shuttle was obtained and thus enabled the transport of a variety of cargos into the central nervous system.     

Organic Spherical Nucleic Acids for the Transport of a NIR‐II‐Emitting Dye Across the Blood–Brain Barrier

DNA nanotechnology plays an increasingly important role in the biomedical field; however, its application in the design of organic nanomaterials is underexplored. Herein, we report the use of DNA nanotechnology to transport a NIR‐II‐emitting nanofluorophore across the blood–brain barrier (BBB), facilitating non‐invasive imaging of brain tumors. Specifically, the DNA block copolymer, PS‐b‐DNA, is synthesized through a solid‐phase click reaction. We demonstrate that its self‐assembled structure shows exceptional cluster effects, among which BBB‐crossing is the most notable. Therefore, PS‐b‐DNA is utilized as an amphiphilic matrix to fabricate a NIR‐II nanofluorephore, which is applied in in vivo bioimaging. Accordingly, the NIR‐II fluorescence signal of the DNA‐based nanofluorophore localized at a glioblastoma is 3.8‐fold higher than the NIR‐II fluorescence signal of the PEG‐based counterpart. The notably increased imaging resolution will significantly benefit the further diagnosis and therapy of brain tumors.     

MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.     

Efficient Cholera Toxin B Subunit‐Based Nanoparticles with MRI Capability for Drug Delivery to the Brain Following Intranasal Administration

Alzheimer's disease (AD) is an incurable neurodegenerative brain disorder that exhibits clear pathologic changes in the hippocampus. Traditional drug delivery systems are ineffective due to the existence of the blood–brain barrier (BBB). In this study, an efficient, stable, and easily constructed nanosystem (CB‐Gd‐Cy5.5) based on the cholera toxin B subunit (CB) is designed to improve the efficiency of drug delivery to the brain, especially the hippocampus. Through intranasal administration, CB‐Gd‐Cy5.5 is easily delivered to the brain without intervention by the BBB. The CB in CB‐Gd‐Cy5.5 is used for specifically combining with the monosialoganglioside GM1, which is widely found in the hippocampus. This nanosystem exhibits impressive performance in accumulating in the hippocampus. In addition, the good magnetic resonance imaging (MRI) capability of CB‐Gd‐Cy5.5 can satisfy the monitoring of AD in the different stages.     

Transparent,Ultrahigh‐Gas‐Barrier Films with a Brick–Mortar–Sand Structure

Transparent and flexible gas‐barrier materials have shown broad applications in electronics, food, and pharmaceutical preservation. Herein, we report ultrahigh‐gas‐barrier films with a brick–mortar–sand structure fabricated by layer‐by‐layer (LBL) assembly of XAl‐layered double hydroxide (LDH, X=Mg, Ni, Zn, Co) nanoplatelets and polyacrylic acid (PAA) followed by CO₂ infilling, denoted as (XAl‐LDH/PAA)_n‐CO₂. The near‐perfectly parallel orientation of the LDH “brick” creates a long diffusion length to hinder the transmission of gas molecules in the PAA “mortar”. Most significantly, both the experimental studies and theoretical simulations reveal that the chemically adsorbed CO₂ acts like “sand” to fill the free volume at the organic–inorganic interface, which further depresses the diffusion of permeating gas. The strategy presented here provides a new insight into the perception of barrier mechanism, and the (XAl‐LDH/PAA)_n‐CO₂ film is among the best gas barrier films ever reported.     

Rabies Virus‐Inspired Metal–Organic Frameworks (MOFs) for Targeted Imaging and Chemotherapy of Glioma

The blood–brain barrier (BBB) restricts access to the brain of more than 98 % of therapeutic agents and is largely responsible for treatment failure of glioblastoma multiforme (GBM). Therefore, it is of great importance to develop a safe and efficient strategy for more effective drug delivery across the BBB into the brain. Inspired by the extraordinary capability of rabies virus (RABV) to enter the central nervous system, we report the development and evaluation of the metal–organic framework‐based nanocarrier MILB@LR, which closely mimicked both the bullet‐shape structure and surface functions of natural RABV. MILB@LR benefited from a more comprehensive RABV‐mimic strategy than mimicking individual features of RABV and exhibited significantly enhanced BBB penetration and brain tumor targeting. MILB@LR also displayed superior inhibition of tumor growth when loaded with oxaliplatin. The results demonstrated that MILB@LR may be valuable for GBM targeting and treatment.     

Multi‐component profiles through the blood–brain barrier in rat after oral administration of over‐the‐counter drug Keke capsule by ultra‐performance liquid chromatography/quadrupole‐ time‐of‐flight MSE method

Keke capsule as a traditional Chinese medicine formulation is used to relieve cough, for analgesia and to reduce bronchial asthma. The multi‐components are absorbed into the blood and brain after oral administration of Keke capsule, with no systematic investigation so far. A reliable and rapid UPLC–QTOF–MS^E combined with a data processing software platform was used to characterize the components of Keke capsule and simultaneously identify bioactive components in blood and brain tissues in rat after oral administration. Consequently, a total of 41 components of Keke capsule, including alkaloids, flavone, flavonols, triterpene, lignanoid, organic acids, glycosides and coumarin were identified. Twenty‐one components were found in plasma, including 18 prototypes and three metabolites; 15 components were found in brain tissues, including 10 prototypes and five metabolites. Alkaloids and flavonoids in Keke capsule were the main components which were absorbed into blood. The main alkaloids of Keke capsule can pass through the blood–brain barrier and show different distribution tendencies in brain tissues. The main components of keke capsule was simultaneously analyzed by throughput analysis, and the corresponding bioactive components were examined by blood‐brain barrier in the rat after oral administration of the capsule.     

Validated UPLC‐MS/MS method for determination of moclobemide in human brain cell supernatant and its application to bidirectional transport study

A simple and sensitive analytical method based on ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) has been developed for determination of moclobemide in human brain cell monolayer as an in vitro model of blood–brain barrier. Brucine was employed as the internal standard. Moclobemide and internal standard were extracted from cell supernatant by ethyl acetate after alkalinizing with sodium hydroxide. The UPLC separation was performed on an Acquity UPLC^TM BEH C₁₈ column (50 × 2.1 mm, 1.7 µm, Waters, USA) with a mobile phase consisting of methanol–water (29.5:70.5, v/v); the water in the mobile phase contained 0.05% ammonium acetate and 0.1% formic acid. Detection of the analytes was achieved using positive ion electrospray via multiple reaction monitoring mode. The mass transitions were m/z 269.16 → 182.01 for moclobemide and m/z 395.24 → 324.15 for brucine. The extraction recovery was 83.0–83.4% and the lower limit of quantitation (LLOQ) was 1.0 ng/mL for moclobemide. The method was validated from LLOQ to 1980 ng/mL with a coefficient of determination greater than 0.999. Intra‐ and inter‐day accuracies of the method at three concentrations ranged from 89.1 to 100.9% for moclobemide with precision of 1.1–9.6%. This validated method was successfully applied to bidirectional transport study of moclobemide blood–brain barrier permeability. Copyright © 2013 John Wiley & Sons, Ltd.     

Involvement of Phytochemical-Encapsulated Nanoparticles’ Interaction with Cellular Signalling in the Amelioration of Benign and Malignant Brain Tumours

Brain tumours have unresolved challenges that include delay prognosis and lower patient survival rate. The increased understanding of the molecular pathways underlying cancer progression has aided in developing various anticancer medications. Brain cancer is the most malignant and invasive type of cancer, with several subtypes. According to the WHO, they are classified as ependymal tumours, chordomas, gangliocytomas, medulloblastomas, oligodendroglial tumours, diffuse astrocytomas, and other astrocytic tumours on the basis of their heterogeneity and molecular mechanisms. The present study is based on the most recent research trends, emphasising glioblastoma cells classified as astrocytoma. Brain cancer treatment is hindered by the failure of drugs to cross the blood–brain barrier (BBB), which is highly impregnableto foreign molecule entry. Moreover, currently available medications frequently fail to cross the BBB, whereas chemotherapy and radiotherapy are too expensive to be afforded by an average incomeperson and have many associated side effects. When compared to our current understanding of molecularly targeted chemotherapeutic agents, it appears that investigating the efficacy of specific phytochemicals in cancer treatment may be beneficial. Plants and their derivatives are game changers because they are efficacious, affordable, environmentally friendly, faster, and less toxic for the treatment of benign and malignant tumours. Over the past few years, nanotechnology has made a steady progress in diagnosing and treating cancers, particularly brain tumours. This article discusses the effects of phytochemicals encapsulated in nanoparticles on molecular targets in brain tumours, along with their limitations and potential challenges.     

Inverted Wedding Cake Growth Operated by the Ehrlich–Schwoebel Barrier in Two‐Dimensional Nanocrystal Evolution

Wedding cake growth is a layer‐by‐layer growth model commonly observed in epitaxial growth of metal films, featured by repeated nucleation of new atomic layers on the topmost surface owing to the confinement of the Ehrlich–Schwoebel (ES) barrier. Herein, we report an inverted wedding cake growth phenomenon observed in two‐dimensional nanostructure evolution. Through a dynamically controlled vapor–solid deposition process of ZnO, a unique basin‐shaped crown was formed on the tip of each nanowire, featured with concentric steps. The atomic steps were nucleated along the edge and propagated toward the center. This is an opposite growth behavior compared to the conventional wedding cake growth, and is thus denoted as inverted wedding cake growth. Through the relation between the crown expansion rate and the temperature, the ES barrier of ZnO was determined to be 0.88 eV. The discovery of inverted wedding cake growth provided insight into the developing nanostructure growth mechanisms.     

Activatable Small‐Molecule Photoacoustic Probes that Cross the Blood–Brain Barrier for Visualization of Copper(II) in Mice with Alzheimer's Disease

Copper enrichment in the brain is highly related to Alzheimer's disease (AD) pathogenesis, but in vivo tracing of Cu²⁺ in the brain by imaging techniques is still a great challenge. In this work, we developed a series of activatable photoacoustic (PA) probes with low molecular weights (less than 438 Da), RPS1 – RPS4 , which can specifically chelate with Cu²⁺ to form radicals with turn‐on PA signals in the near‐infrared (NIR) region. Introducing the electron‐donating group N,N‐dimethylaniline into the probe was found to significantly enhance the radical stability and PA intensity. The best probe in the series, RPS1 , showed a fast response (within seconds) to Cu²⁺ with high selectivity and a low PA detection limit of 90.9 nm . Owing to the low molecular weight and amphiphilic structure, RPS1 could effectively cross the blood–brain barrier (BBB) and thus allowed us, for the first time, to visualize Cu²⁺ in vivo via PA imaging in the brains of AD mice.     

Thermogelling behaviors of poly(caprolactone‐b‐ethylene glycol‐b‐caprolactone) triblock copolymer in the presence of hyaluronic acid

In this article, we studied the effect of hyaluronic acid (HA) on thermogelation of poly(caprolactone‐b‐ethylene glycol‐b‐caprolactone) (PCL‐PEG‐PCL) aqueous solution designed as an injectable system for prevention of postsurgical tissue adhesion. The PCL‐PEG‐PCL triblock copolymers were simply synthesized by ring‐opening polymerization of ε‐caprolactone (CL) in the presence of PEG as a polymeric initiator. The synthesized copolymers were confirmed by proton nuclear magnetic resonance (¹H‐NMR) spectroscopy. Possible interactions between HA and PCL‐PEG‐PCL triblock copolymers in the blend were evaluated by Fourier‐transform infrared spectroscopy (FTIR). The effect of HA on the micellization of PCL‐PEG‐PCL aqueous solution was investigated by dye solubilization method and electrophoretic lighting scattering (ELS) spectrophotometer. Also, the thermogelling behaviors of the PCL‐PEG‐PCL triblock copolymers in the presence of HA and their mechanism were investigated by test tube inverting method, ¹³C‐NMR, ¹H‐NMR, Advanced Rheometic Expansion System (ARES), and differential scanning calorimetry (DSC). The PCL‐PEG‐PCL/HA blend aqueous solutions undergo the sol‐gel‐sol transition in response to an increase in temperature (10–60 °C) and the gelation of the PCL‐PEG‐PCL was rather accelerated by HA. Presumably, this accelerated gelation seems to arise from the attractive interactions between them and the effect of chain confinement in the micelle corona region. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 3629–3637, 2008     

Potential‐Energy Surfaces,the Born–Oppenheimer Approximations,and the Franck–Condon Principle: Back to the Roots

The concept of a potential‐energy surface (PES) is central to our understanding of spectroscopy, photochemistry, and chemical kinetics. However, the terminology used in connection with the basic approximations is variously, and somewhat confusingly, represented with such phrases as “adiabatic”, “Born–Oppenheimer”, or “Born–Oppenheimer adiabatic” approximation. Concerning the closely relevant and important Franck–Condon principle (FCP), the IUPAC definition differentiates between a classical and quantum mechanical formulation. Consequently, in many publications we find terms such as “Franck–Condon (excited) state”, or a vertical transition to the “Franck–Condon point” with the “Franck–Condon geometry” that relaxes to the excited‐state equilibrium geometry. The Born–Oppenheimer approximation and the “classical” model of the Franck–Condon principle are typical examples of misused terms and lax interpretations of the original theories. In this essay, we revisit the original publications of pioneers of the PES concept and the FCP to help stimulate a lively discussion and clearer thinking around these important concepts.     

Structural characterization of the aquaporin inhibitor 2‐nicotinamido‐1,3,4‐thiadiazole

Nicotinamides are a class of compounds with a wide variety of applications, from use as antimicrobial agents to inhibitors of biological processes. These compounds are also cofactors, which are necessary components of metabolic processes. Structural modification gives rise to the activities observed. Similarly, 1,3,4‐thiadiazoles have been shown to possess antioxidant, antimicrobial, or anti‐inflammatory biological activity. To take advantage of each of the inherent characteristics of the two aforementioned functional groups, 2‐nicotinamido‐1,3,4‐thiadiazole, C₈H₆N₄OS, was synthesized. Since defining chemical connectivity is paramount in understanding biological activity, in this report, the structural characterization of 2‐nicotinamido‐1,3,4‐thiadiazole has been carried out using X‐ray crystallographic methods. The NMR‐derived assignments were made possible by utilizing one‐ (1D) and two‐dimensional (2D) NMR techniques. In addition, UV–Visible and IR spectroscopies, and elemental analysis were used to fully characterize the product synthesized by the one‐step reaction between nicotinoyl chloride hydrochloride and 2‐amino‐1,3,4‐thiadiazole. Computational parameters related to blood–brain barrier permeability are also presented.